Benzopyranquinolinol derivatives and process for their production



United States Patent Office 3,518,273 BENZOPYRANQUINOLINOL DERIVATIVES AND PROCESS FOR THEIR PRODUCTION Maximilian von Strandtmann, Rockaway, Marvin P. Cohen, New Milford, and John Shavel, Jr., Mendham, N.J., assignors to Warner-Lambert Pharmaceutical Company, Morris Plains, N.J., a corporation of Delaware No Drawing. Filed Aug. 3, 1966, Ser. No. 569,832 Int. Cl. C07d 39/00 U.S. Cl. 260-289 8 Claims ABSTRACT OF THE DISCLOSURE Pyran derivatives of the formula:

(III) are disclosed wherein R and R are each lower alkyl, aralkyl, aryl or R and R taken together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine or morpholine nucleus; Z represents a carbocyclic or heterocyclic nucleus; R is hydrogen, lower alkyl, halogen; R and R are each hydrogen, lower alkyl, aralkyl, aryl; or R and R taken together form with the second and third carbon atom of the pyran ring, a saturated aliphatic ring such as cyclopentane, cyclohexane or cycloheptane; R is hydrogen or lower alkyl.

The compounds of this invention are useful as intermediates for the production of other pyran derivatives which are useful as anti-microbial agents.

This invention relates to pyran derivatives of the formula:

(III) wherein R and R are each lower alkyl, aralkyl, aryl or R and R taken together with the nitrogen atom to which they are attached form a piperidine, pyrrolidine or morpholine nucleus; Z represents a carbocyclic or heterocyclic nucleus such as pyridine, naphthalene, benzene, naphthoquinone, coumarin, isoquinoline quinoline and the like; R is hydrogen, lower alkyl, halogen such as chlorine, bromine or fluorine, or lower alkoxy; R and R are each hydrogen, lower alkyl, aralkyl, aryl; or R and R taken together form with the second and third carbon atom of the pyran ring a saturated aliphatic ring such as cyclopentane, cyclohexane or cycloheptane, norbornane,

3,518,273 Patented June 30, 1970 or a partially reduced aromatic ring such as indan, Tetralin or Decalin; R is hydrogen or lower alkyl.

The term lower alkyl and the lower alkyl portion of the term lower alkoxy employed herein are to be understood to mean a straight or branched chain alkyl group having from 1 to 7 carbon atoms, e.g. methyl, ethyl, isopropyl, butyl, hexyl, heptyl, etc. The term aryl means monohomocyclic or monoheterocyclic ring such as phenyl, pyridyl and the like; and aralkyl means aryl lower alkyl wherein aryl and lower alkyl are as defined such as phenyl lower alkyl or pyridyl lower alkyl.

The symbols R R R R and R and R used hereinafter have the same meaning as defined.

This invention also encompasses within its scope a novel process for the production of the above compounds.

In addition, the compounds of this invention are useful as intermediates for the production of other pyran derivatives of the formula:

R5 on I which may be prepared from compound III by hydrolysis. Compounds bearing the Formulas III and IV exhibit antimicrobial activity against gram positive bacteria and hypoten'sive activity. In order to use these compounds about 1 part by weight of the active ingredient is combined with 99% by weight of a inert carrier such as talc or petrolatum to form dosage forms suitable for topical application. They may also be combined with a pharmaceutical carrier to form dosage forms such as tablets, capsules, solutions and the like with the active ingredient being present from 1 to 1000 mg. per dosage unit. The compounds also exhibit anti-protozoal activity such as against species of plasmodia. Compound IV is also embraced within the scope of this invention. Compounds of type IV may be also obtained by a direct condensation of a phenolic Mannich base with a ketone or aldehyde.

Those compounds of Formula IV where R is hydrogen can be dehydrated to compounds of Formula V according to scheme R CIIZN/ 2 \nl I n 2 I with an enamine of the formula preferably in chemically equivalent amounts.

The reaction is etfected by heating the respective reactants in an inert solvent such as diozane at the reflux temperature of the solvent employed. The desired reaction product is recovered from the mother liquor by suitable techniques such as evaporation of the reaction solvent.

The above-described reaction may be used for the preparation of a wide variety of heterocyclic compounds which contain a pyran ring such as pyrano [3,2-b]pyridine, naphtho[2,1b]pyran, benzopyrano [3,2-b] pyridine, pyrano[3,2-c] [l]benzopyran, naphtho[2,3-b]pyran, benzo- [a] xanthene, benzopyrano [3,2-f] quinoline, benzopyrano- [4,3-b] [1]benzopyran, pyrano[3,2-f] quinoline, benzopyrano[3,2-h]quinoline and the like.

These are representative of the many types of compounds that may be prepared depending on the Mannich bases and enamines used in the reaction. For example, employing an enamine derived from aldehyde to react with the Mannich base, the compounds obtained may be depicted by the following schematic outline.

(1) With hydrolysis:

A CH3 CH 0H-.-N I It OH H H N\ O o 3 CH3 0 0 H CH2 CH3 H CH2 CH3 on, H20 A 0H, 1

Type III Type IV (2) Without hydrolysis:

CE: I! CH: CH:

CHzN

Type III 4 On the other hand employing an enamine derived from a ketone, the reaction may be depicted by the following outline:

OH JHN OH \/\0 N CHa TypeIII l H20 1120/ U on TypeIV The Mannich bases used as the starting material are prepared by standard methods described in a-Aminoalkylierung by H. Hellmann and G. Opitz, Verlag Chemie G.rn.b.H., Weinheim, 1960.

The enamines used as the starting materials are prepared by standard methods according to G. Stork et al. (J. Am. Chem. Soc., 85, 207 (1963)) from amines such as dialkylamines, pyrrolidine, morpholine, piperidine, and the like.

In order to further illustrate the practice of this invention, the following examples are given. The temperatures referred to therein are in degrees centigrade.

EXAMPLE 1 8,9,10, 1 1,1 1 a, l 2-hexahydro-7al-pyrrolidinyl) 7aH-benzo [a] xanthene The solution of 10 g. of 1dimethylaminomethy1-2- naphthol and 7.5 g. of cyclohexanone pyrrolidine enamine in 50 ml. of dioxane was refluxed for 5 days. The solvent was removed in vacuo and the gummy residue was recrystallized from ethyl acetate, M.P. -95 yield 8 g. (52%); A m (6) 232 (75,600), 266 (4,200), 277 (5,000), 289 (3,900), 317 (2,100), 333 (2,600); 'y 740 (ms.),-810 (ms.), 880 (m.), 940 (m.), 990 (ms.), 1150 (m.), 1210 (ms.), 1235 (ms.), 1600 (m.), 1620 ms.) cmf AnaIysis.Calcd. for C H NO (percent): C, 82.04; H, 8.20; N, 4.56. Found (percent): C, 81.79; H, 8.28; N, 4.50.

EXAMPLE 2 7a,8,9,10,11,1 1a-hexahydro-7H-[1]'benzopyrano- [3,2-h]quinolin-11a-ol The solution of 10.1 g. of 7-dimethylaminomethyl-8- quinolinol, and 7.55 g. of cyclohexanone pyrrolidine enamine in 50 ml. of dioxane was refluxed for 4 days. The mixture was treated with ml. of H 0, and refluxed for 2 hr. and chilled. The crystalline precipitate was filresidual gum was recrystallized from abs. ethanol, M.P. 132-135; yield 2.5 g. A m (9) 246 (49,600), 308 (2,800); 790 (ms.), 325 (ms.), 915 (s.), 1090 (s.), 1110 (m.), 1210 (m.), 1505 (m.), 3150 (ms) cm.-

Analysis.-Calcd. for C H NO (percent): C, 75.27; H, 6 .71; N, 5.49. Found (percent): C, 75.37; H, 6.85; N. 5.40.

EXAMPLE 3 8,9,10,11,11a,12-hexahydro-7aH-[1]benzopyrano- [3,2-f]quinolin-7a-ol The solution of 15 g. of 5-dimethylaminornethyl-6- quinolinol and 11.3 g. of pyrrolidine enamine of cyclohexanone in 75 m1. of dioxane was refluxed for 4 days. The mixture was treated with 15 ml. of H 0, refluxed for 2 hrs. and chilled. The crystalline precipitate was filtered and recrystallized from abs. ethanol, M.P. 238- 240"; yield 16 g. (83%); x my. (6) 241 (44,500), 285 (2,920), 327 (3,520); 'y 810 (ms.), 955 (s.), 975 (s.), 1020 (ms.), 1050 (ms.), 1135 (ms.), 1230 (ms.), 1600 (m.), 1615 (m.), 3100 (ms.) cmf Analysis.-Calcd. for C13H17N02 (percent): C, 75.27; H, 6.71; N, 5.49. Found (percent): C, 75.18; H, 6.95; N, 5.50.

EXAMPLE 4 3,4-dihydro-3,3-dimethyl-2H-pyrano[3,2-b] pyridin-2-ol The solution of 7.5 g. of 2-dimethylaminomethyl-3- hydroxypyridine and 5 g. of N,N-dimethylisobutenylamine in 50 ml. of dioxane was refluxed for 13 days. The mixture was treated with 10 ml. of H 0, and refluxed for 2 hr. The solvents were removed in vacuo, and the residual gum was crystallized from ethyl acetate, M.P. 114-117; yield 3 g. (33%); x mu (5) 219 (11,100), 258 (4,625), 280 (3,600), 326 (3,180); 'y 710 (m.), 795 (ms.), 950 (s.), 1090 (ms.), 1110 (ms.), 1190 (ms.), 1240 (ms.), 1580 (mw.), 1590 (rnw.) cmf Analysis.Calcd. for C H NO (percent): C, 67.02; H, 7.31; N, 7.82. Found (percent): C, 67.17; H, 7.38; N, 7.86.

6 EXAMPLE 5 2,3 -dihydro2,2-dimcthyl-3-morpholino- 1H- naptho [2, H3] pyran The solution of 10.5 g. of 1-dimethylaminomethyl2- F naphthol, and 7.05 g. of l-N-morpholino-l-isobutene in 50 ml. of dioxane was refluxed for one week. The solution Was treated with 10 ml. of water and refluxed for 2 hr. The solvents were removed in vacuo and the residue was crystallized from acetonitrile, M.P. 154-156"; yield 7 g. (50%); x m (e) 235 (68,200), 267 (4,800), 278 (5,200), 290 (4,000); 740 (ms.), 805 (ms.), 915 (ms.), 925 (ms.), 985 (ms.), 1030 (m.), 1110 (s)., 1235 (ms.), 1595 (m.), 1620 (111.)CII1."]'.

Analysis.Calcd. for C H NO (percent): C, 76.73; H, 7.80; N, 4.71. Found (percent): C, 76.69; H, 7.75; N, 4.70.

EXAMPLE 6 6,7,8,9,9a,10-hexahydro-5aH-[1]benzopyrano[3,2-b] pyridin-Sa-ol The solution of 7.6 g. of 2-dimethylaminomethylpyrid- 3-ol, and 7.55 g. of pyrrolidine enamine of cyclohexanone was refluxed for 2 Weeks. The solution was treated with 10 ml. of H 0, and refluxed for 2 hr. The solvents were removed in vacuo and the crystalline residue recrystallized from ethyl acetate, M.P. 153-157.5; yield 3.9 g. (39%); x m (6) 220 (6,210), 281 (5,550), 325 (580); 'y 790 (ms.), 870 (m.), 95055 doublet (s.), 1105 (m.), 1255 (s.), 1595 (m.), 3025 (ms) cmf Analysis.-Calcd. for C H NO (percent): C, 70.22; H, 7.37; N, 6.82. Found (percent): C, 70.45; H, 7.44; N, 6.55.

EXAMPLE 7 3,4-dihydro-2-hydroxy-3 ,3-dimethyl-2H,5H-pyrano [3,2-c] 1] benzopyran-S-one The solution of 11 g of 3-dimethylaminomethyl-4- hydroxycoumarin and 5 g. of 'N,N-dimethylisobutenylamine in 50 ml. of dioxane was refluxed for 96 hr. After an addition of 10 ml. of H 0, the mixture was refluxed for 2 hrs. and the solvents were removed in vacuo. The residual gum was chromatographed in a column of 400 g. of Florisil using ethyl acetate as the eluent. The crystalline fractions were combined and recrystallized from ethyl acetate, M.P. 139; yield 5 g. (40%); 1 m (e) 269 10,500), 281 (12,100 305 (10,500 319 (7,000); v 745 (m.), 895 (ms.), 1045 (ms.), 1170 (m.), 1580 (m.), 1630 (s.), 1685 (s.), 3400 (ms) cm.

Analysis.Calcd. for C H O (percent): C, 62.28; H, 5.73. Found (percent): C, 68.55; H, 5.91.

7 EXAMPLE 8 3,4-dihydro-2-hydroxy-3 ,3-dirnethyl-2H-naphtho [2,3-b] pyran-5,10-dione O OH H \H/\/ CH:

The solution of 11.5 g. of 3-dimethylarninomethyl-2- hydroxy-1,4-naphthoquinone and 5 g. of N,N-dimethylisobutenylamine in 50 m1. of dioxane was refluxed for 4 days. The solution was treated with ml. of H 0 and refluxed for 2 hr. The solvents were removed in vacuo and the residue was recrystallized from abs. ethanol with the aid of charcoal, M.P. 191-193"; yield 5.5 g. (42%); A m (6) 251 (23,600), 281 (13,600), 331 (2,880); 'y 740 (m.), 870 (m.), 950 (ms.), 1065 (ms.), 1190 (ms.), 1580 (m.), 1595 (m.), 1620 (ms.), 1650 (ms.), 1675 (ms.), 3450 (ms.) cmf Analysis.Calcd. for C H O (percent): C, 69.75; H, 5.46. Found (percent): C, 70.04; H, 5.63.

EXAMPLE 9 3,4-dihybro-3,3-dimethyl-Z-morpholino-ZH-naphtho [2,3-b]pyran-5,10-dione H V CH: 0

This was prepared from 3-dimethylaminomethyl-2-hydroxy 1,4 naphthoquinone, and N morpholino-lisobutene in analogous fashion to 3,4-dihydro-3,3-dimethyl 2 morpholino-2H,5H-pyrano[3,2-c][l]benzopyran-S-one. Recrystallized from ethyl acetate, M.P. 153-154.5; yield 43%; A mp. (e) 250 (24,000), 279 (14,700), 331 (2,860); 'y 720 (ms.), 850 (m.), 955 (ms.), 1115 (ms.), 1195 (ms.), 1250 (ms.), 1575 (m.), 1590 (m.), 1620 (ms.), 1640 (ms.), 1675 (ms.), cmf Analysis.Calculated for C H NO (percent): C, 69.70; H, 6.47; N, 4.28. Found (percent): C, 69.85; H, 6.63; N, 3.98.

EXAMPLE 10 8 ,9, 10, 1 1,1 1a, l2-hexahydro-7a-H-benzo [a] xanthen-7a-o1 The solution of 10.5 g. of l-dimethylaminomethyl-Z- naphthol and 7.55 g. of pyrrolidine enamine of cyclohexanone in 50 ml. of dioxane was refluxed for one week. Ten ml. of water was added and reflux was continued for 2 hr. The solvents were removed in vacuo and the residual gum was triturated with hot acetonitrile. The crystalline precipitate was filtered off and recrystallized from abs. ethanol, M.P. 143.5-145"; yield 4.4 g. (35%); A m, E 222 (76,000), 277 5,200 289 4,100 'y 750 (ms.), 770 (m.), 815 (ms.), 960 doublet (ms.),

EXAMPLE 11 7a,8,9,10,11,11a-hexahydro-1la-hydroxy-6H,7H[1] benzopyr'ano[4,3 -b] [1]benzopyran-6-one The solution of 11 g. of 3-dimethylaminomethyl-4-hydroxycoumarin and 7.5 g. of pyrrolidine enamine of cyclohexanone in 50 ml. of dioxane was refluxed for 4 days. The mixture was treated with 10 ml. of H 0, and refluxed 2 hr. The solvents were removed in vacuo. The gummy residue was extracted with hot ethyl acetate and the ethyl acetate soluble material was chromatographed on 300 g. of florisil with ethyl acetate development. The fractions which crystallized on concentration were combined, filtered, and recrystallized from absolute ethanol, M.P. -194"; A III/.0 (E) 269 (10,200), 281 (11,900), 304 (10,700), 317 (7,300); 'y 750 (ms.), 860 (m.), 935 (ms.), 1040 doublet (m.), 1180 (m.), 1270 (m.), 1580 (ms.), 1610 (ms.), 1620 (s.), 1675 (s.), 3375 (m.) cm.-

Analysis.Calculated for C H O (percent): 70.57; H, 5.92. Found (percent): C, 70.55; H, 6.18.

EXAMPLE 12 (Method B) 7a,8,9,10,11,1la-hexahydro-l1a-hydroxy-6H,7H-[1] benzopyrano [4,3-b] benzopyran-6-one The solution of 11 g. 3 dimethylaminomethyl-4-hydroxycoumarin and 4.9 g. of cyclohexanone in 50 ml. of dioxane was refluxed for 3 days. The solvent was removed in vacuo and the residue recrystallized from acetonitrile, M.P. 190-94"; yield 6 g. (44%).

EXAMPLE 13 1,2-dihydro-2,2-dimethyl-3H-pyrano [3,2-f] quino1in-3-ol This was prepared from 5 g. of S-dimethylaminomethyl-6-hydroxyquinoline, and 2.5 g. of N,N dimethylisobutenylamine in analogous fashion to 8,9,10,11,11a-12- hexahydro-7aH-[1]benzopyrano[3,2-b]quinolin 7a-o1. Recrystallized from ethyl acetate, M.P. 20l.5203.5; yield 2.3 g. 40%); x my (9) 241 43,000), 286 (3,000), 327 (3,600); 'y 795 (ms.), 825 (ms.), 985

EXAMPLE 14 8,9,10,11-tetrahydro-12H-benzo[a]xanthene The solution of 5 g. of 8,9,10,11,11a,12-hexahydro- 7aH-benzo[a]xanthen-7a-ol and 5 g. of anhydrous so dium acetate in 50 ml. of glacial acetic acid was refluxed for 5 hr., and poured into an ice-water mixture. The precipitate was filtered off, washed with water and recrystallized from abs. ethanol, M.P. 92.5-95"; yield 3.7 g. (79%); x ma (6) 2.15 (46,000), 219 51,000), 244 (19,400), 283 (4,000), 322 (1,600), 336 (1,700); 'y 755 (m.), 810 (m.), 1120 (m.), 1195 (ms.), 1220 (ms.), 1515 (mw.), 1605 (m.), 1625 (rnw.), 1730 (mw.) cmf AIvalysis.-Calcd. for C H O' (percent): C, 86.40; H, 6.83. Found (percent): C, 86.53; H, 6.94.

EXAMPLE 15 9,10,1l,12-tetrahydro-8H[1]benzopyrano 3 ,2-f] quinoline This compound was prepared in analogous fashion to 8,9,1'0,11-tetrahydro-12H-benzo[a]xanthene from g. of 8,9,10,1l,11a,12 hexahydro 7aH[1]benzopyrano- [3,2-b]quinolin-7a-ol, M.P. 130-32"; yield 3 g. (63%); A m, (e) 254 (19,700), 336 (2,880); 'y 800 ms), 835 (ms.), 1110 (m.), 1190 (m.), 1230 (m.), 1500 (m.), 1615 (rnw.), 1710 (mW.) cm.-

Analysis.--Calcd. for C H NO (percent): C, 80.98; H, 6.37; N, 5.90. Found (percent) C, 81.09; H, 6.37; N, 5.80.

EXAMPLE 16 3,4-dihydro-3,3-dimethyl-2H-pyrano- [3,2-h1quinolin-2-ol A CH3 I CH3 C@ 10 (13%); A III/.1. (e) 244 (48,900), 308 (2,840); A/max 790 (m.), 970 (ms.), 1080 (ms.), 1505 (m.), 3175 (m.) CH1.1.

AnaIysis.-Calcd. for C H NO (percent): C, 73.34; H, 6.59; N, 6.11. Found (percent): C, 73.27; H, 6.78; N, 6.34.

EXAMPLE 17 3 ,4-dihydro-3,3-dimethyl-2-morpholino-2H,5H- pyrano 3,2-c] 1]benzopyran-5-one The solution of 11 g. of 3-dimethylaminornethyl-4-hydroxycoumarin and 7.05 g. of l-N-morpholino-l-isobutene in 50 ml. of dioxane was refluxed for 72 hr. The solvent was removed in vacuo, and the residual gum was recrystallized from ethyl acetate, M.P. 142-144; yield 6 g. (38%); A m (e) 269 (10,200), 281 (11,900), 305 (10,600), 318 (7.300); 'y 745 (m.), 850 (m.), 1040 (m.), 1110 (m.), 1175 (m.), 1630 (ms.), 1690 (ms) cmf Analysis.Calcd. for C H NO (percent): C, 68.55; H, 6.71; N, 4.44. Found (percent): C, 68.66; H, 6.84; N, 4.72.

What is claimed is:

1. Compounds of the formulas:

R H IV R T Solution of of 7-dimethylaminomethyl's' wherein R and R are each independently n-lower alkyl,

quinolinol, and 5 g. of N,N-dimethylisobutenylarnine in 5 0 ml. of dioxane was refluxed for 3 days. The mixture was treated with 10 m1. of water, refluxed for 2 hr., and evaporated in vacuo. The crystalline residue Was rephenyl lower alkyl, pyridyl lower alkyl or phenyl; Z is quinoline or isoq-uinoline; R is hydrogen, lower alkyl, halogen or lower alkoxy; R and R are each independently hydrogen, lower alkyl, phenyl lower alkyl or crystallized from abs. ethanol, M.'P. 18386; yield 1.5 g. phenyl; and R and R taken together with the second and third carbon atom of the pyran ring form cycloalkyl of from 5 to 7 carbons, or a partially reduced aromatic ring selected from iudau, tetralin or decalin; R is hydrogen or lower alkyl.

2. The compound of claim 1 which is 7a,8,9,10,11,11ahexahydro-7H-[1]-benzopyrano[3,2-h1quinolin-1la-ol.

3. The compound of claim 1 in which 8,9,10,11,11a,12- hexahydro-7 aH-[ l benzopyrano [3,2-f] quinolin-7a-o1.

4. The compound of claim 1 which is 1,2-dihydro-2,2- dimethyl-3H-pyrano 3,2-f quinolin-3-ol.

5. The compound of claim 1 which is 9,10,11,12-tetrahydro-8H[1]benzopyrano[3,2-f1quinoline.

6. The compound of claim 1 which is 3,4-dihydro-3,3- dimethyl-2H-pyrano [3,2-h] quinolin-Z-ol.

7. Process for the production of a compound of the formula:

N R R wherein R and R are each independently n-lower alkyl, phenyl lower alkyl, pyridyl lower alkyl, or phenyl; Z is quinoline or isoquinoline; R is hydrogen or lower alkyl, halogen or lower alkoxy; R and R are, each independently hydrogen, lower alkyl, phenyl lower alkyl or phenyl; and R and R taken together with the second and third carbon atom of the pyran ring form cycloalkyl of from to 7 carbons or a partially reduced aromatic ring selected from indau, tetralin or decalin; R is hydrogen or lower alkyl, which comprises contacting a compound of the formula:

R CI-IZN/ 2 R with a compound of the formula:

8. Process for the production of a compound of the formula:

5 H 4 &1

o N 6 l z with water under refluxing conditions.

References Cited UNITED STATES PATENTS 2,358,287 9/1944 Hromatka 2603452 3,121,086 2/1964 Sartori 260289 3,337,563 8/1967 Skaletzky 2602947 3,336,340 8/1967 Freimillor 260345.2 X 3,337,563 8/1967 Skaletzky 260294.7 3,419,561 12/1968 Jenkins 260289 X OTHER REFERENCES Von Strandtmann et al., Tetra Nedron Letters No. 35, pp. 3103-6 (1956).

Ahuja et al., abstracted in (Nem ABSSR, vol. 45, co]. 6206-7 (1951).

Von Strandtmann et al., abstracted in Chem. Abstr., vol. 63, col. 18059(d) (1965).

DOUGLAS G. DAUS, Primary Examiner US. Cl. X.R. 

